The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide-resistant Streptococcus pneumoniae. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.
The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:
EP 216,169 and U.S. Pat. No. 4,826,820 to Brain et al. disclose antibacterially active 6-carbamate erythromycin derivatives stated to xe2x80x9chave antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.xe2x80x9d
U.S. Pat. No. 5,444,051, U.S. Pat. No. 5,561,118, and U.S. Pat. No. 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formulae 
wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.
U.S. Pat. No. 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.
WO 97/17356 (Or et al.) discloses tricyclic erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.
WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula 
wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.
WO 99/21864 (Or et al.) discloses 6,11-bridged erythromycin derivatives having antibacterial activity.
The invention provides compounds of Formula 1: 
wherein:
R1 and R2 are independently selected from hydrogen, optionally substituted C1-C8-alkyl, optionally substituted xe2x80x94CH2C2-C8-alkenyl, and optionally substituted xe2x80x94CH2C2-C8-alkynyl, wherein the substituents are selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, xe2x80x94COORa, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94NRaRb, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein Ra and Rb are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R1 and R2 are not both hydrogen;
R3 is selected from hydrogen;
R4 is selected from hydrogen, halogen, and hydroxy;
R5 is hydrogen or a hydroxy protecting group;
R6 is selected from hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
X and Xxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and
Y and Yxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, xe2x80x94CHOH, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula 1.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
Relative to the above description, certain definitions apply as follows.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless specified otherwise, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, and xe2x80x9calkynyl,xe2x80x9d whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbons. xe2x80x9cAlkenylxe2x80x9d refers to a straight or branched chain hydrocarbon with at least one carbon-carbon double bond. xe2x80x9cAlkynylxe2x80x9d refers to a straight or branched chain hydrocarbon with at least one carbon-carbon triple bound. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. xe2x80x9cAlkoxyxe2x80x9d radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. xe2x80x9cCycloalkylxe2x80x9d groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. The alkyl, alkenyl, alkynyl, cycloalkyl group and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94COORa, xe2x80x94NRaRb, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein Ra and Rb are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl.
The term xe2x80x9cacylxe2x80x9d as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term xe2x80x9cAcxe2x80x9d as used herein, whether used alone or as part of a substituent group, means acetyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo and iodo. (Mono-, di-, tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.
xe2x80x9cArylxe2x80x9d or xe2x80x9cAr,xe2x80x9d whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d denotes phenyl.
Whether used alone or as part of a substituent group, xe2x80x9cheteroarylxe2x80x9d refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, N-oxo-pyridyl, 1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, and thienothienyl. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.
The terms xe2x80x9cheterocycle,xe2x80x9d xe2x80x9cheterocyclic,xe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated, partially saturated, or non-aromatic cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolinyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; 2-oxazepinyl; azepinyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; benzothiopyranyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; benzopyranyl; dihydrobenzopyranyl; indolinyl; chromonyl; coumarinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.
Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.
Designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The term xe2x80x9chydroxy protecting groupxe2x80x9d refers to groups known in the art for such purpose. Commonly used hydroxy protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is incorporated herein by reference. Illustrative hydroxyl protecting groups include but are not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethythiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethyl silyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl; acyl and aroyl such as acetyl, pivaloylbenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acylaryl.
Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
The phrase xe2x80x9ca pharmaceutically acceptable saltxe2x80x9d denotes one or more salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicyclic acid and the like. Suitable salts are furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)2, Al(OH)3, piperidine, morpholine, ethylamine, triethylamine and the like.
Included within the scope of the invention are the hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate, and sesquihydrate forms. The present invention also includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal. As a particular embodiment, the subject is a human.
The term xe2x80x9cdrug-resistantxe2x80x9d or xe2x80x9cdrug-resistancexe2x80x9d refers to the characteristics of a microbe to survive in presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.
The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.
In particular, compounds of Formula 1 wherein R1 and R2 are independently selected from hydrogen, substituted C1-C8-alkyl, substituted xe2x80x94CH2C2-C8-alkenyl, and substituted xe2x80x94CH2C2-C8-alkynyl, wherein the substituents are selected from CN, nitro, xe2x80x94COORa, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94NRaRb, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein Ra and Rb are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R1 and R2 are not both hydrogen;
R3 is selected from hydrogen;
R4 is selected from hydrogen, halogen, and hydroxy;
R5 is hydrogen or a hydroxy protecting group;
R6 is selected from hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thoalkyl group;
X and Xxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and
Y and Yxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, xe2x80x94CHOH, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl; are embodiments of the present invention for such purposes. More particularly, R2 is hydrogen, R4 is hydrogen or fluorine, X and Xxe2x80x2 form Cxe2x95x90O together with the carbon atom to which they are attached, and Y and Yxe2x80x2 form Cxe2x95x90O together with the carbon atom to which they are attached.
Compounds of Formula 1, which are represented by Formula 1xe2x80x2
wherein R1, R2, R3, and R4 are as described above are also embodiments of this invention. More particularly, R2 and R3 are hydrogen and R4 is fluorine.
Compounds of Formula 1, which are represented by Formula 1xe2x80x3
wherein R1, R2, R3, and R4 are as described above, are further embodiments of this invention. More particularly, R2 and R3 are hydrogen and R4 is fluorine.
Compounds of Formula 1, wherein R5 may be selected from acyl and aroyl are further embodiments of this invention.
The following are yet other embodiments of the present invention for such purposes:
Carbamic acid, [(2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-xcex2-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester;
Carbamic acid, [(2E)-3-[4-(1-methyl-1H-pyrazol-3-yl)phenyl]-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-xcex2-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester;
Carbamic acid, [(2E)-3-(4-pyrazinylphenyl)-2-propenyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-xcex2-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester; and
Carbamic acid, [3-[4-(2-pyrimidinyl)phenyl]propyl]-, (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-10-[[3,4,6-trideoxy-3-(dimethylamino)-xcex2-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester.
This invention also provides processes for preparing the instant compounds. The compounds of Formula I may be prepared from readily available starting materials such as erythromycin and erythromycin derivatives well known in the art. Outlined in Schemes 1 through 11 are representative procedures to prepare the compounds of the instant invention: 
Scheme 1 illustrates the method of synthesis of the 2xe2x80x2,4xe2x80x3-diacetyl-6-carbamyl-11,12-dideoxy-11,12-iminocarbonyloxyerythromycin A (VI) and the 2xe2x80x2-acetyl-6-carbamyl-11,12-dideoxy-3-O-descladinosyl-11,12-iminocarbonyloxyerythromycin A (1a) precursors to the compounds of the invention.
Erythromycin A is treated with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 48 hours to afford 2xe2x80x2,4xe2x80x3,11-triacetylerythromycin A (I). The 10,11-anhydro derivative (II) can be readily obtained by treatment of I with a base in an inert solvent such as THF, dioxane, DME, or DMF at a temperature ranging from xe2x88x9278xc2x0 C. to 80xc2x0 C. for 1-24 hours. Suitable bases to effect the elimination reaction include, but are not limited to, sodium hexamethyidisilazide, potassium hexamethyldisilazide, LDA, lithium tetramethylpiperidide, DBU, and tetramethylguanidine. It will be apparent to one skilled in the art that alternative methods for synthesis of 2xe2x80x2,4xe2x80x3-diacetyl-10,11-anhydroerythromycin A are available, including conversion of erythromycin A to the 11,12-cyclic carbonate derivative with ethylene carbonate, followed by elimination with tetramethylguanidine, as described in Hauske, J. R. and Kostek, G., J. Org. Chem. 1982, 47, 1595. Selective protection of the 2xe2x80x2 and 4xe2x80x3-hydroxyl groups can then be readily accomplished with acetic anhydride in the presence of a tertiary amine base. Likewise, alternative protecting group strategies may be employed. For example, erythromycin A may be treated with benzoic anhydride, propionic anhydride, or formic acetic anhydride under similar conditions as described above to obtain the 2xe2x80x2,4xe2x80x3,11-triacylated erythromycin A derivative followed by elimination to afford the corresponding 10,11-anhydro compound.
Once the suitably protected 10,11-anhydro derivative is obtained, derivatization of both tertiary hydroxyl groups can be carried out by treatment with trichloroacetylisocyanate in an inert solvent, such as methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 1-24 hours to yield the di-(N-trichloroacetyl)carbamate derivative (III). The N-trichloroacetylcarbamate functionalities can be hydrolyzed to the corresponding primary carbamates by treatment with a suitable base, such as triethylamine, in an aqueous solvent mixture, such as methanol/water for 1-24 hours at a temperature ranging from 20xc2x0 C. to 80xc2x0 C. Alternative bases may likewise be used to effect this conversion, such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Under the reaction conditions, the primary carbamate formed at the 12-position undergoes spontaneous Michael addition to the electrophilic 11-position of the xcex1,xcex2-unsaturated ketone and the 2xe2x80x2-acetoxy group is hydrolyzed to the corresponding hydroxyl to afford the cyclic carbamate derivative (IV). Compound IV is generally isolated as a mixture of methyl epimers at the C10-position, which can be readily converted to the desired C10-xcex2-methyl epimer (V) by treatment with an equilibrating base, such as potassium t-butoxide, tetramethylguanidine, or DBU in a suitable solvent, such as THF, dioxane, DME, DMF or t-butanol at a temperature ranging from xe2x88x9278xc2x0 C. to 80xc2x0 C. for 1 to 24 hours. Reprotection of the 2xe2x80x2-hydroxyl group to give VI can be carried out by treatment with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and optionally an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 48 hours. It is understood that an orthogonal protection strategy of the sugar hydroxyls may also be employed by treatment of V with alternate reagents such as benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl chloride. Finally, selective removal of the cladinose sugar can be accomplished by reaction of VI with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water to afford 1a. Reaction time is typically 0.5-24 hours at a temperature ranging from xe2x88x9210xc2x0 C. to 37xc2x0 C. 
Scheme 2 depicts synthesis of compounds of formulae 1b, 1c and 1d, wherein RCHO is an aldehyde (R may be a member of the group including, but not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkenyl, arylalkynyl, aralkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkynyl, and heterocycloalkyl). Oxidation of the 3-hydroxy group of 1a to yield compound 1b can be effected with DMSO and a carbodiimide, such as EDCl, in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Removal of the 2xe2x80x2-acetyl group of compound 1b is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. to yield compound 1c. Alternative methods for deprotection of the 2xe2x80x2-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. Compounds of formula 1d can be obtained by selective alkylation of the primary carbamate of 1c with a suitably substituted aldehyde in the presence of a reducing agent and acid. Alternatively, the corresponding acetal may be used in place of the suitably substituted aldehyde in this reaction. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. 
It will be clear to one skilled in the art that the order of the steps in the synthetic sequence leading to compounds of the invention can be altered, provided that the functionality present in the molecule is compatible with the desired selective transformations. This is illustrated in Scheme 3. For example, compound 1a can be treated under similar conditions as described above for the reductive alkylation of compound 1c (Scheme 2) to yield compounds of the formula 1e. Removal of the 2xe2x80x2-acetyl group of compound 1e as described for the conversion of compound 1b to compound 1c (Scheme 2) provides compounds of formula 1g. Alternatively, oxidation of the 3-hydroxyl of compound 1e to the ketone of compound 1f can be conducted as described for the analogous transformation of 1a to 1b in Scheme 2. Finally, deprotection of the 2xe2x80x2-acetyl group of 1f is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2) to provide the compounds of formula 1d, wherein R is as previously defined. 
Scheme 4 illustrates an alternate route for the preparation of the compounds of the invention (1d). Reaction of compound VI with a suitably substituted aldehyde and a reducing agent, such as triethylsilane, in the presence of an acid, such as trifluoroacetic acid, in a suitable solvent, such as acetonitrile, methylene chloride, or toluene, at a temperature ranging from xe2x88x9220xc2x0 C. to 100xc2x0 C. for 2-96 hours leads to the simultaneous removal of the cladinose sugar and the selective alkylation of the primary carbamate to afford compound 1e. Alternatively, the corresponding acetal of the suitably substituted aldehyde may be used to effect this transformation. Conversion of compound 1e to compound 1f and compound 1f to compound 1d can be conducted as described above. 
Scheme 5, wherein R4a is halogen and R is as described above, illustrates the procedures by which compounds of formula 1b can be converted to compounds of formula 1j.
Fluorination of compound 1b can be accomplished with any one of a number of fluorinating reagents, including N-fluorobenzenesulfonimide in the presence of base, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis[tetrafluoroborate] (SELECTFLUOR(trademark)) in the presence of base, 10% F2 in formic acid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate, 3,5-dichloro-1-fluoropyridinium triflate, (CF3SO2)2NF, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base, N-fluoropyridinium triflate, and N-fluoroperfluoropiperidine in the presence of base to give 1h wherein R4a is F. Chlorination of 1b can be effected with hexachloroethane in the presence of base, sulfuryl chloride, thionyl chloride, trifluoromethanesulfonyl chloride in the presence of base, chlorine, or sodium hypochlorite in the presence of acetic acid to give 1h wherein R4a is Cl. Suitable brominating agents would include pyridinium hydrobromide perbromide, bromine in acetic acid, N-bromosuccinimide in the presence of base, 1,2-dibromoethane in the presence of base, or carbon tetrabromide in the presence of base to give 1h wherein R4a, is Br. Suitable iodinating agents include N-iodosuccinimide in the presence of base or iodine to give 1h wherein R4a is l.
Transformation of the halogenated derivatives 1h to the corresponding compounds of formula 1j can be accomplished through analogous synthetic routes as above. Reaction of 1h with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid yields compounds 1i. Reagent combinations for effecting this transformation include triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds 1i are then converted to the corresponding compounds of formula 1j by reaction with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C.
It will be understood by one skilled in the art of organic synthesis that the halogenation reaction can also be conducted at a later stage in the synthetic sequence. For example, halogenation of compound 1f (Scheme 3) affords the corresponding 2-halo derivative, which likewise can be converted to compounds of the invention by deprotection of the 2xe2x80x2-acetyl group under the previously described conditions. 
Schemes 6A and 6B illustrate the procedures by which compounds of the formula 1b can be converted to 2xcex1- and 2xcex2-fluoro derivatives of formulae 1n and 1q. Fluorination of compound 1b can be accomplished as described herein above. Reagent combinations for the conversion of compound 1b to the 2xcex1-fluoro derivative 1k include SELECTFLUOR and sodium hexamethyldisilazide in DMF and N-fluorobenzenesulfonimide and potassium t-butoxide in THF. Typically, the reaction is conducted at xe2x88x9278xc2x0 C. to xe2x88x9260xc2x0 C. for 5 minutes to 24 hours. Reagent combinations for the conversion of compound 1b to the 2xcex2-fluoro derivative 1o include N-fluorobenzenesulfonimide and sodium hydride in DMF. Typically, this reaction is conducted at 0xc2x0 C. to 20xc2x0 C. for 1 to 24 hours.
Transformation of the fluorinated derivatives 1k and 1o to the corresponding compounds of the invention 1n and 1q, respectively, can be accomplished through analogous synthetic routes as above. Reaction of 1k or 1o with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid yields compounds 1m and 1p, respectively. Reagent combinations for effecting this transformation include triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds 1m and 1p are then converted to the corresponding compounds of the invention 1n and 1q, respectively, by reaction with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C.
It will be also understood by one skilled in the art of organic synthesis that the fluorination reaction can also be conducted at a later stage in the synthetic sequence. For example, fluorination of compound 1f (Scheme 3) affords the corresponding 2-fluoro derivative, which likewise can be converted to compounds of the invention by deprotection of the 2xe2x80x2-acetyl group under the previously described conditions.
Other compounds of the invention may also be suitable substrates for further transformation to yield other compounds of the present invention. Some of these transformations are illustrated in Schemes 7-11. 
Scheme 7 illustrates the conversion of the 3-(4-nitrophenyl)-2-propenyl analog (1r) to the 3-[4-(4H-1,2,3-triazol-4-yl)phenyl]-2-propenyl analog (1t) via the intermediacy of the 3-(4-aminophenyl)-2-propenyl derivative (1s) wherein R4 is as described above. The selective reduction of the nitro group of 1r to the amine of 1s can be conducted with tin(II) chloride in ethanol at a temperature ranging from 20xc2x0 C. to 78xc2x0 C., typically for 1 to 24 hours. Alternative methods for reduction of the nitro group can also be employed, including iron/hydrochloric acid, iron/acetic acid, tin/hydrochloric acid, zinc/ammonium chloride, or sodium borohydride/nickel chloride. Conversion of the amino group of 1s to the 1,2,4-triazole of 1t is effected by condensation of the amine with N,N-dimethylformamide azine dihydrochloride in the presence of a base, such as pyridine. Reaction time is typically 2 to 72 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 115xc2x0 C. 
Scheme 8 depicts the conversion of 3-(4-bromophenyl)-2-propenyl analog (1u) to the 3-(1,1xe2x80x2-biphen-4-yl)-2-propenyl analog (1v) wherein R4 is as described above. Reaction of the aryl bromide with an aryl boronic acid derivative to give the biaryl derivative is conducted under typical Suzuki coupling conditions, i.e., in the presence of a Pd0 catalyst, typically palladium tetrakistriphenylphosphine, and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Aryl iodides and aryl triflates are also suitable substrates for this conversion. 
Scheme 9 illustrates the conversion of a substituted N-propenylcarbamate derivative (1w) to the corresponding substituted N-propylcarbamate compound (1x), wherein Rxe2x80x2 may be a member of the R group except alkenyl and alkynyl, and R and R4 is as described above. Typically, this transformation is conducted via catalytic transfer hydrogenation, in which the olefin is reacted with ammonium formate in the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as methanol or ethanol, at a temperature ranging from 20xc2x0 C. to 60xc2x0 C. for 15 minutes to 24 hours. Other methods for reduction of the double bond could also be applicable, for example treatment with hydrogen in the presence of a noble metal catalyst, such as palladium or platinum. It will be obvious to one skilled in the art that the analogous N-propynylcarbamate may likewise be reduced to the corresponding N-propylcarbamate under similar conditions. 
Scheme 10 illustrates a method for conversion of a secondary carbamate derivative (1j) to a tertiary carbamate derivative (1y), wherein Rxe2x80x3 is an independent member of the R group, and R and R4 are as described above, by reaction with an aldehyde and a suitable reducing agent, typically triethylsilane, in the presence of an acid, typically trifluoroacetic acid, in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene. Reaction times are typically 2 to 96 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Alternative methods for effecting this conversion may also be contemplated, for example reaction of a suitably protected secondary carbamate precursor with an alkyl halide in the presence of a sufficiently strong base, such as sodium hydride, potassium hexamethyldisilazide, or LDA. 
Scheme 11 illustrates the conversion of compounds 1d, wherein R is as previously defined, to compounds containing a 2-hydroxy substituent (1z). This transformation may be conducted by treatment of compound 1d with charcoal in the presence of air in a suitable solvent, such as methanol or ethanol. It will be apparent to one skilled in the art of organic synthesis that other methods may be employed to effect this conversion, including for example treatment of 1d with a base, such as potassium hexamethyidisilazide or LDA, and an oxidant, such as camphorsulfonyloxaziridine or MoOPh. 
Scheme 12 illustrates the conversion of 1axe2x80x2 to compounds of the invention 1bxe2x80x2, 1cxe2x80x2, 1dxe2x80x2, 1exe2x80x2, 1fxe2x80x2, and 1gxe2x80x2 with a nitrogen-containing substituent on the carbamate in the 6-position, wherein R4 and Ra are as described above. Reaction of 1axe2x80x2 with a protected aminoaldehyde derivative, such as N-(benzyloxycarbonyl)glycinal, in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid affords the protected amine derivative (1bxe2x80x2). Typically this reaction is conducted in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene, for 2 to 96 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Deprotection of 1bxe2x80x2 to afford the corresponding amine derivative (1cxe2x80x2) can be readily effected by procedures known in the art, such as catalytic hydrogenation in the presence of a noble metal catalyst or catalytic transfer hydrogenation with palladium on carbon in the presence of cyclohexadiene or ammonium formate at a temperature ranging from 20xc2x0 C. to 60xc2x0 C. Typically these reactions are conducted in an inert solvent such as methanol or ethanol. Conversion of 1cxe2x80x2 to several of the compounds of the invention (Scheme 12) can be conducted with techniques known in the art, such as reductive alkylation with formaldehyde in the presence of a suitable reducing agent, such as sodium cyanoborohydride, and an acid, such as acetic acid to afford the alkylated amine derivative (1dxe2x80x2). Alternatively, 1cxe2x80x2 may be converted to the amide derivative (1exe2x80x2) by acylation with a suitably substituted acid chloride or acid anhydride in the presence of a base, such as pyridine, optionally in the presence of an acylation catalyst, such as DMAP. Amine derivative (1cxe2x80x2) may also converted to a carbamate (1fxe2x80x2) by treatment with a suitably substituted chloroformate or pyrocarbonate derivative in the presence of pyridine. Finally, reaction of 1cxe2x80x2 with a suitably substituted isocyanate in an inert solvent, such as tetrahydrofuran or methylene chloride, provides access to the correponding urea derivatives (1gxe2x80x2). Optional deprotection of the 2xe2x80x2-acetyl group of 1bxe2x80x2, 1cxe2x80x2, 1dxe2x80x2, 1exe2x80x2, 1fxe2x80x2, and 1gxe2x80x2 is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2). 
Scheme 13 illustrates the analogous procedure whereby 1axe2x80x2 is converted to compounds of the invention 1hxe2x80x2, 1ixe2x80x2, 1jxe2x80x2, and 1kxe2x80x2 with a carbonyl-containing substituent on the carbamate in the 6-position, wherein R4 and Ra are as described above. Reaction of 1axe2x80x2 with, for example, benzyl 4-oxobutanoic acid (Cannon, J. G. and Garst, J. E., J. Org. Chem. 1975, 40, 182) in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid affords the benzyl ester derivative (1hxe2x80x2). Typically this reaction is conducted in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene, for 2 to 96 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Deprotection of 1hxe2x80x2 to afford the corresponding acid derivative (1ixe2x80x2) can be readily effected by procedures known in the art, such as catalytic hydrogenation in the presence palladium on carbon in an inert solvent such as methanol or ethanol. Conversion of 1ixe2x80x2 to other compounds of the invention (Scheme 13) can be executed with techniques known in the art, such as reaction with a suitably substituted alcohol or amine in the presence of a coupling agent such as dicyclohexylcarbodiimide, BOP, or PyBOP, optionally in the presence of a base, such as diisopropylethylamine, and an acylation catalyst, such as DMAP or HOAt, to afford the corresponding ester derivative (1jxe2x80x2) or amide derivative (1kxe2x80x2). Optional deprotection of the 2xe2x80x2-acetyl group of 1hxe2x80x2, 1ixe2x80x2, 1jxe2x80x2, and 1kxe2x80x2 is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2).
When the aldehydes or acetals used in the preparation of compounds 1d, 1e, 1i, 1m, 1p, and 1y are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions. Exemplary syntheses of several of the aldehydes used in the preparation of 1d, 1e, 1i, 1m, 1p, and 1y are presented hereinafter as reference examples.
Compounds of the invention wherein R3 is a group other than H may be prepared as described in WO 98/25942.
Compounds of the invention wherein R5 is a hydroxy protecting group other than acyl may be prepared in methods analogous to those shown in the above schemes with appropriate reagents that are either commercially available or may be made by known methods.
Compounds of the invention wherein R6 is a group other than ethyl may be prepared beginning with modified erythromycin derivatives as starting materials as described in various publications including, but not limited to, WO99/35157, WO00/62783, WO00/63224, and WO00/63225.
These compounds have antimicrobial activity against susceptible and drug resistant Gram positive and Gram negative bacteria. In particular, they are useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly activity against S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococci, Moraxella catarrhalis and H. influenzae. These compounds are particularly useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.
Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol.17, No.2, xe2x80x9cMethods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobicallyxe2x80x94Fourth Editionxe2x80x9d, which is incorporated herein by reference.
In this method two-fold serial dilutions of drug in cation adjusted Mueller-Hinton broth are added to wells in microdilution trays. The test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5xc3x97104 CFU/well.
Following inoculation of the microdilution trays, the trays are incubated at 35xc2x0 C. for 16-20 hours and then read. The MIC is the lowest concentration of test compound that completely inhibits growth of the test organism. The amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray. As set forth in Table 1, compounds of the present invention were tested against a variety of Gram positive and Gram negative pathogenic bacteria resulting in a range of activities depending on the organism tested.
Table 1 below sets forth the biological activity (MIC, xcexcg/mL) of some compounds of the present invention.
This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.
When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
Compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, which may be given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 2000 mg. Dosage forms suitable for internal use comprise from about 100 mg to 1200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).